U.S. patent application number 10/092954 was filed with the patent office on 2003-09-11 for convection-enhanced drug delivery device and method of use.
Invention is credited to Dextradeur, Alan J., Konieczynski, David D., Rohr, William L..
Application Number | 20030171738 10/092954 |
Document ID | / |
Family ID | 27754038 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030171738 |
Kind Code |
A1 |
Konieczynski, David D. ; et
al. |
September 11, 2003 |
Convection-enhanced drug delivery device and method of use
Abstract
An implantable drug delivery system includes an infusion pump
assembly with a fluid outlet, a fluid delivery pathway extending
from the pump outlet to a target tissue site; and a controlled
release material unit positioned in the fluid delivery pathway to
release a drug or bioactive material into the delivery pathway. The
pump assembly delivers fluid as a high flow infusion flow in said
pathway, entraining drug material released by the release unit and
establishing a pressure gradient at the distal end of the pathway
that results in convection-enhanced transport such that the
released drug(s) or treatment material enter the target tissue site
with enhanced penetration depth and/or concentration. The pump
delivers a carrier fluid that may reside in an external or in an
implanted reservoir, or that may be an endogenous fluid, such as
plasma or CSF.
Inventors: |
Konieczynski, David D.;
(Needham, MA) ; Dextradeur, Alan J.; (Franklin,
MA) ; Rohr, William L.; (Marshfield, MA) |
Correspondence
Address: |
NUTTER MCCLENNEN & FISH LLP
WORLD TRADE CENTER WEST
155 SEAPORT BOULEVARD
BOSTON
MA
02210-2604
US
|
Family ID: |
27754038 |
Appl. No.: |
10/092954 |
Filed: |
March 6, 2002 |
Current U.S.
Class: |
604/891.1 ;
604/500 |
Current CPC
Class: |
A61M 5/14276 20130101;
A61M 25/0075 20130101; A61M 2202/0464 20130101 |
Class at
Publication: |
604/891.1 ;
604/500 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. An implantable drug delivery system, comprising: an infusion
pump including a fluid outlet; a fluid delivery pathway effective
for extending from the fluid outlet to a discharge portion
positionable at a target tissue site; and a controlled release drug
assembly, said drug assembly being configured for controllably
releasing drug material, and communicating with said fluid delivery
pathway such that the drug material is released into said fluid
delivery pathway, wherein the pump assembly is effective to deliver
a carrier fluid to the fluid outlet such that the drug material
released into the fluid pathway discharges at the discharge portion
to treat the target tissue site.
2. The system of claim 1, wherein the pump further comprises a
power source.
3. The system of claim 1, wherein the pump includes a chamber for
holding a predetermined quantity of carrier fluid.
4. The system of claim 1, further comprising a chamber having a
concentrated delivery agent, and configured to release the delivery
agent into carrier fluid.
5. The system of claim 1, further comprising a mixing chamber
operative to mix a drug or delivery agent in carrier fluid.
6. The system of claim 1, wherein the pump further includes an
inlet pathway for delivering said carrier fluid to the pump, said
pump being effective to convey the fluid from the inlet to the
outlet.
7. The system of claim 1, wherein the controlled release drug
assembly is a microchip having at least one drug reservoir, and
wherein the microchip is in fluid communication with the fluid
delivery pathway intermediate to the pump and the target tissue
site.
8. The system of claim 7, wherein the microchip is located in the
fluid delivery pathway.
9. The system of claim 1, wherein the controlled release drug
assembly is located outside the fluid delivery pathway.
10. The system of claim 1, wherein the carrier fluid is a fluid
selected from the group consisting of a physiological buffer, a
pharmaceutical excipient or adjuvant, an endogenous fluid, and
combinations thereof.
11. The system of claim 10, wherein the carrier fluid is an
endogenous fluid selected from the group consisting of cerebral
spinal fluid, blood, lymphatic fluid, components thereof, and
combinations thereof.
12. The system of claim 6, wherein the inlet pathway includes a
separate catheter positionable in tissue for delivering an
endogenous fluid to the pump.
13. The system of claim 12, wherein the separate catheter, the pump
and the fluid delivery pathway are dimensioned for positioning in
tissue to form an endogenous fluid circulation loop.
14. The system of claim 1, where in the infusion pump includes a
microcontrol unit that controls flow rate of the pump.
15. The system of claim 1, wherein the infusion pump is effective
to pump at a rate to drive convection-enhanced transport into the
target tissue site, thereby enhancing effective delivery profile at
the target site.
16. The system of claim 1, wherein the flow rate ranges from about
0.5 to about 20 microliters per minute.
17. The system of claim 1, wherein the pump assembly includes a
pump assembly selected from among the group consisting of a
pressurized reservoir, a peristaltic pump, a diaphragm pump, and a
piston pump.
18. The system of claim 12, wherein the separate catheter is
configured to collect endogenous fluid from a donor site selected
from the group of sites consisting of the central nervous system,
the circulatory system and the lymphatic system.
19. The system of claim 1, wherein the drug release assembly
includes a microchip powered by a power source.
20. The system of claim 14, wherein the microchip is in
communication with the microcontrol unit.
21. The system of claim 12, wherein the controlled release drug
assembly includes a microchip having a microprocessor that is in
communication with the microcontrol unit.
22. The system of claim 1, wherein the drug release assembly
includes a microchip containing one or more drugs therein.
23. The system of claim 22, wherein the drug release assembly
includes a reservoir having a cap positioned over a drug contained
therein, wherein release of the drug is controlled by diffusion
through or disintegration of the cap.
24. The system of claim 23, wherein the drug release assembly
includes a microchip having a microprocessor/controller, and
diffusion through or disintegration of the cap is controlled by the
microprocessor/controller.
25. The system of claim 1, wherein the drug release assembly is a
microchip having a plurality of reservoirs containing plural
different drugs, drug concentrations, or a combination thereof.
26. The system of claim 1 further comprising one or more
biosensors, and wherein the system responds to a biosensor
signal.
27. The system of claim 1, wherein the drug release assembly
includes plural controllable release sites positioned within a wall
of the fluid delivery pathway.
28. The system of claim 1 further comprising an array of biosensors
disposed in tissue, and wherein at least one of the infusion pump
and the controlled drug release assembly responds to biosensor
signals from the array.
29. A method for infusing a drug into a target tissue site of a
subject, the method comprising the steps of: providing an infusion
pump assembly, wherein the pump assembly includes a carrier fluid
source, wherein the infusion pump assembly is effective to convey a
fluid within the pump through a fluid delivery pathway to a target
tissue site; providing a drug release assembly in communication
with the fluid delivery pathway, said release assembly having at
least one drug reservoir configured for controlled release of a
drug into the fluid delivery pathway; and enabling a carrier fluid
to be delivered under pressure from the infusion pump assembly at a
desired flow rate through the fluid delivery pathway to transport
drug released by the drug release assembly to the target tissue
site.
30. The method of claim 29, wherein the pump assembly is effective
to deliver carrier fluid at a rate effective to induce convective
bulk transport of the drug into tissue at the target site.
31. The method of claim 30, wherein the target site is brain tissue
and the pump assembly is effective to deliver carrier fluid at a
rate in the range of about 0.5 to about 20 microliters/minute to
induce convective bulk transport of the drug into brain tissue.
32. The method of claim 29, wherein the fluid delivery pathway
terminates in a distal end, wherein the distal end is implantable
within the target site.
33. The method of claim 29, wherein the one or more drugs are
released in a delivery regimen selected from among a pulsatile, an
intermittent and a continuous delivery regimen.
34. The method of claim 29, further including the step of providing
a biosensor in at least one of the fluid delivery pathway, the
tissue site and the controlled release assembly, and controlling at
least one of the infusion pump assembly and the drug release
assembly in response to biosensor signals.
35. The method of claim 29, further including the step of detecting
a material or condition with a biosensor array, and controlling at
least one of the infusion pump assembly and the drug release
assembly in response thereto.
36. The method of claim 29, wherein the carrier fluid is selected
from the group consisting of a physiological buffer, a
pharmaceutical excipient or adjuvant, an endogenous fluid, and
combinations thereof.
37. The method of claim 29, wherein the carrier is an endogenous
fluid selected from the group consisting of cerebral spinal fluid,
blood, lymphatic fluid, components thereof, and combinations
thereof.
38. The method of claim 29, wherein the infusion pump assembly is
operable to continuously maintain enhanced fluid pressure over a
predetermined period of time.
39. The method of claim 29, wherein a microcontrol unit disposed
within the infusion pump controls fluid delivery pressure profile
over a predetermined period of time.
40. A method of delivering a drug or bioactive material to target
tissue such as tissue of the central nervous system (CNS), such
method comprising the steps of providing an infusion pump having an
output connectable with a delivery line implantable at a target
tissue site; and providing a controlled release drug device
attachable in communication with the delivery line, such that the
controlled release drug device is effective to release drug into
carrier fluid pumped by the infusion pump; thereby delivering the
carrier fluid to the target tissue site with said drug, the pump
being controllable to maintain an elevated delivery pressure such
that the drug achieves a convectively enhanced profile in tissue at
the target tissue site.
Description
FIELD OF THE INVENTION
[0001] This invention pertains to an implantable device and method
for delivery of a drug or bioactive material into a target tissue
of a subject, such as to a locus in the subject's brain, or other
desired organ or tissue location within a subject's body.
BACKGROUND OF THE INVENTION
[0002] The treatment of a disease often involves prescribing one or
more drugs for an afflicted individual. Medication schedules can
vary depending upon a number of factors. There are conditions which
require that different drugs be taken throughout the day. There are
diseases which require that a patient take a series of medications
throughout their lifetime. Some medical conditions require the
direct administration of the drug to its target site, for example,
because appropriate concentrations cannot be attained by systemic
administration, or, as in the case of the central nervous system
("CNS"), systemic administration does not reach the target site. In
all of these situations, it is important that drug delivery be
accomplished in a rapid and efficient manner.
[0003] In the case of the CNS, it is not unusual that in many
instances the direct route of administration is preferred. Ehrlich
in 1885 described an almost impenetrable barrier to the CNS. This
barrier is commonly referred to as the blood-brain barrier. This
blood-brain barrier is selective with respect to what molecules can
enter the CNS from the general circulation. As a result, many drugs
used to treat CNS diseases cannot reach their intended target
without modifying their structure in some manner.
[0004] To circumvent this difficulty of entry, direct
administration of the drug into the CNS is often performed. One
modality for accomplishing this is to use a syringe containing the
desired drug and inject it into the cerebral spinal fluid ("CSF"),
or into brain parenchyma. Alternatively, an implanted drug delivery
system can be employed which uses an infusion catheter that is
inserted within the CNS to directly deliver a material to the CSF
or brain parenchyma. Often, the relevant drug or bioactive material
is to be delivered to a localized region at extremely small dosage,
and may be delivered at predetermined intervals throughout the day,
or delivered in response to a physiological signal, e.g., in
response to detection of a certain level of a protein, or a
metabolite in the blood.
[0005] In many such systems a pump is activated to move the drug or
bioactive material, usually contained in a physiological buffer,
from a drug reservoir into an implanted infusion catheter, and the
drug travels through the catheter until it is delivered to the
target site. Once at the site, the drug is released from the
catheter and enters the target tissue, typically by a diffusion
mechanism. This delivery mechanism, typically involving an
implanted delivery catheter, is especially useful for targeting
tumors, wherein a chemotherapeutic or other treatment agent is to
be selectively applied to the tumor. Other areas of active interest
involve treatment of certain chronic or degenerative brain tissue
conditions, and other conditions of the CNS. Several implantable
infusion pumps have been proposed or developed for delivering a
drug or bioactive material to the brain to effect various
treatments.
[0006] The ability to implant a drug delivery system capable of
selectively delivering multiple small doses of a drug, or doses of
different drugs, has been realized in part also by the advent of
microchip technology. A microchip device may include a plurality of
drug reservoirs that are etched into or otherwise formed in a
biocompatible implantable substrate, and are filled with the
intended drug(s). A number of reservoirs are formed in a single
microchip, and release of material from each reservoir is
separately controlled, for example, by a barrier membrane or other
controllable member that controllably effects release of the drug
from the reservoir. This technology significantly enhances the
versatility of implantable drug delivery technology. Reservoirs may
be filled with different drugs, and the reservoirs can be capped
with materials that either degrade or allow the drugs to diffuse
passively out of the reservoir over time. Moreover, this capping
material can be structured such that upon application of an
electric potential, it erodes quickly, changes permeability or
otherwise responds to the signal to release the active agent. The
sites and times of this active release can then be controlled by a
remote controller, by an integrally implanted programmed
microprocessor, by an implanted but externally programmable unit,
or other effective arrangement. The resulting power source and
timing control can be compactly and robustly configured, resulting
in an effective structure without the complex mechanical structure
or large space requirements of a typical infusion pump.
[0007] Microchip drug devices are well suited to holding and
dispensing multiple small doses of a drug or drugs. However, a
limitation of current microchip drug delivery systems is that
generally only small amounts of material enter the targeted organ,
or permeate the targeted site within the organ. Typically, the drug
is released from a reservoir housed within the microchip, and the
drug travels into or over a target tissue region by a diffusion
process, often competing against a clearance reaction having a rate
which may be comparable to the release rate. This mode of delivery
may therefore have an effective tissue penetration range of only a
millimeter or less over many hours, or may result in substantially
diminishing concentration as diffusion proceeds. The diffusion
transport depends primarily on a free concentration gradient and
the diffusivity of the dispensed drug in the target tissue.
Generally, high molecular weight molecules such as antibodies tend
to have a low diffusion rate, while low molecular weight molecules,
although typically having greater diffusivity, are also susceptible
to being cleared more quickly from the target site because of the
ease of their entry into the capillary system. Thus for many
potentially desirable applications, the penetrable/treatable tissue
range and the treatment concentration profiles achievable by
microchip delivery are severely limited.
[0008] There remains a need for an efficient implantable drug
delivery system effective to selectively deliver one or more drugs
to a target site.
[0009] There also exists a need for a drug delivery system that
extends the range and/or concentration profile for delivery of
doses of drugs to the CNS.
SUMMARY OF THE INVENTION
[0010] One or more of the foregoing and other desirable ends are
achieved in accordance with the present invention by an implantable
drug delivery system, including an infusion pump assembly and a
controlled release biomaterial delivery unit, such as a microchip
delivery device. The infusion pump assembly delivers a carrier
fluid to a fluid outlet, and a fluid delivery pathway extends from
the outlet past the controlled release material delivery unit to a
distal ported outlet, which is implanted at a target tissue site.
The controlled release delivery device, positioned in or in
communication with the fluid delivery pathway, releases a drug or
bioactive material into the carrier fluid which is delivered by the
infusion pump assembly at a rate effective to establish a local
pressure gradient in the region of the ported outlet at the tissue
site, so that the drug is delivered into, and preferably
convectively driven by bulk transport, into the tissue at the
target site. The carrier may be, e.g., a biologically inert or
inactive fluid such as physiologic saline, or it may be an
endogenous body fluid. Thus, the infusion pump assembly
advantageously provides a high flow infusion flow such that when
the fluid bearing the drug or bioactive material exits the catheter
near the target site, the drug undergoes convection driven
transport and enhanced penetration into the target tissue site.
[0011] The distal end of the catheter is implanted providing a
fixed site of drug administration, and it extends such that one or
more ports of the catheter open in the immediate vicinity of the
target site, which may, for example, be a tumor site, a nerve, a
lesion or other targeted region of affected brain or other tissue.
The controlled release delivery unit and optionally the infusion
pump may also be implanted, but these units need not be in the
immediate vicinity of the target tissue. Thus, for example, when
the target tissue is a brain lesion or tumor, the distal catheter
may be stereotactically implanted in or adjacent the tumor through
a cranial hole to release the carrier-borne drug in parenchymal
spaces, while the other components of the system may be implanted
subdermally, and connect to the near end of the delivery
catheter.
[0012] Thus, the controlled release unit is fitted in-line with the
more proximal portion of the delivery catheter such that the
carrier fluid flow from the pump entrains material released from
the release unit and the fluid then passes out via the port(s) of
the distal end of the delivery catheter, or via an extension
delivery conduit, at the target tissue site. The ported distal
catheter assembly may be a needle-like assembly, such as a
stainless steel or stiff polymer tube having elongated ports that
release the drug over an extended site, while the more proximal
catheter portions may be formed of one or more segments of polymer
tubing of a suitable stiffness to dependably transmit microdose or
microflow volumes of carrier from the pump through, past or over,
the drug release device without loss of pressure. The pump may
connect to several such delivery catheters, and these may have
their distal ends implanted close to each other to enlarge the
treated tissue volume of a single tissue region or organ;
alternatively, the plural delivery catheters may be implanted at
distinct sites. One or more sensors may be associated with the
delivery catheter or catheters to report drug concentration, tissue
condition or the like to a processor which may operate the pump
and/or control the drug release unit.
[0013] In some embodiments, the controlled release unit may be
formed in a wall of the catheter itself. For example, it may be
implemented as a plurality of recessed sites constituting drug
release reservoirs formed in the catheter wall, each site holding
one or more desired drug(s) in a degradable polymer or other matrix
material, or holding the drug separated from the fluid pathway by a
degradable or a controlled porosity membrane, or in other
controlled-release form. Alternatively, the controlled release unit
may be a separate unit, i.e., a microchip having a structure
connected to but independent of the catheter. Another embodiment
provides the drug release unit as a replaceable release cartridge
that fits within the fluid delivery pathway (e.g., the delivery
catheter), and may be conveniently replaced when depleted without
disturbing the implanted catheter. In some embodiments, the release
unit may couple to the fluid path via a manifold or a set of
separate passages effective to channel the fluid pumped by the
infusion pump over or through all, or appropriate ones of, its
release reservoirs and into the distal delivery catheter.
[0014] The fluid supply to the inlet of the infusion pump may be an
implanted reservoir or other supply. In one embodiment, a reservoir
is implanted subdermally and possesses a cover or septum formed of
a self-sealing polymer. The reservoir is refillable through the
patient's skin by piercing the septum with a syringe to deliver a
refill volume of the carrier fluid. The reservoir may also be a
pressurized assembly, such as a pressure-driven bellows, in which
case the infusion pump assembly may be implemented by a simply
providing one or more valves, restrictors or other elements that
regulate the time and/or the rate at which fluid is allowed to pass
from the reservoir. Alternatively, the infusion pump may be an
electrically powered assembly, having a power source and a
controller. In accordance with another aspect of the invention, the
pump may receive fluid from a fluid supply line or inlet catheter
that is positioned to draw the body's endogenous fluid, for
example, the patient's cerebrospinal fluid, into the pump as the
carrier medium for drug delivery. This arrangement advantageously
utilizes naturally compatible fluid, and requires neither a
reservoir nor the periodic replenishment of the carrier. Moreover,
when applied to an isolated body system such as the central nervous
system, this embodiment advantageously at least partially offsets
the volumes of fluid withdrawn and returned to the central nervous
system, thus promoting isobaric fluid conditions in the skull or
spinal column.
[0015] Other or further embodiments of the invention may include a
chamber in the pump assembly that contains a concentrated delivery
agent, which it supplies into the pumped carrier fluid. A mixing
chamber may be provided to allow mixing of drugs before they are
pumped to the tissue site. This is especially advantageous for
multidrug regimens in which several incompatible or mutually
unstable drugs are to be delivered at once, or in which
concentration must be closely controlled.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] These and other features of the invention will be understood
from the description and claims below, taken together with the
figures showing illustrative embodiments, wherein:
[0017] FIG. 1 illustrates a first embodiment of a drug delivery
system of the present invention;
[0018] FIG. 1A illustrates a another embodiment of a drug delivery
system of the present invention;
[0019] FIG. 1B illustrates a another embodiment of a drug delivery
system of the present invention;
[0020] FIG. 2 illustrates another embodiment of a drug delivery
system of the present invention;
[0021] FIG. 2A illustrates another embodiment of a drug delivery
system of the present invention;
[0022] FIG. 3 illustrates another embodiment of a drug delivery
system of the present invention; and
[0023] FIG. 3A schematically illustrates another embodiment of a
drug delivery system of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0024] FIG. 1 schematically illustrates a system 10 of the present
invention for delivering a drug or treatment material to the
central nervous system. The system includes an infusion reservoir
or source 24 of fluid connected through a pump, valve or flow
initiator/controller 25 to a controlled release drug delivery
device (such as a microchip drug delivery device) 30 and then
through a site delivery catheter 40 to deliver a drug, via ports at
the distal end of the catheter, to a target tissue site. The system
is configured to treat a localized tissue site in a patient's body,
e.g., the central nervous system, and the catheter is implanted
such that the fluid exits through one or more openings in its
distal end region at the target tissue site and permeates through
targeted tissue to effectively treat the targeted region. Thus, the
region of effective tissue treatment is defined by the catheter
placement. This may be placed at a site such as a brain tumor or
diseased region of the brain, at a tumor to deliver a
chemotherapeutic agent, at an organ to deliver an organ-specific
treatment, at a nerve location to treat chronic pain, or at another
suitable local site. The distal end portion of the catheter 40 may
be a thin gauge needle-like tube having one or more elongated ports
extending therealong. When the target tissue site is in the brain,
catheter 40 may be implanted using a stereotactic frame to position
it such that its ports lie adjacent to or extend centrally through
the target site.
[0025] The reservoir 24 or supply and the pump, valve or controller
25 together form the infusion pump 20. The precise pump structure
may be flexibly implemented with any suitable structure as known in
the art, either with an electromechanically-actuated peristaltic or
displacement pumping mechanisms, or with a pressurized reservoir or
osmotically-driven source connected to a control valve or
restrictor assembly to regulate the provision of fluid into the
fluid delivery path. In either case, whether powered by pressure or
electromechanically, the infusion pump assembly produces an
accurately administered and sustainable flow of a total volume of
fluid at a suitable infusion flow rate, discussed further below,
such as a rate of about 0.5 to about 20.0 microliters per minute
for a typical infusion delivery tube. The fluid itself may simply
be a carrier, or it may include a drug or other active material
within a carrier fluid. The carrier may be an inert or
non-bioactive fluid, such as physiological buffer or saline, or may
contain materials, such as adjuvants or the like to enhance use as
a carrier and drug delivery vehicle. In one embodiment described
below, the carrier may be a physiological fluid such as
cerebrospinal fluid (CSF). One or more drugs or other bioactive
materials are then provided directly into the flow path by the
release unit 30.
[0026] The controlled release unit 30 delivers one or more drugs or
other agents at controlled times or over controlled intervals. This
unit may be a microchip device, for example, of the type shown in
U.S. Pat. No. 5,797,898 of Santini, Jr. et al. That is, unit 30 may
be a miniaturized multi-well drug delivery device 32 with a
plurality of reservoirs 31, 33, 35, and controller 32a configured
to effect release from appropriate ones of the wells at appropriate
times. The controller may operate in accordance with a programmed
instruction set (via a fixed PROM) to operate at predetermined
times, or may have a signal receiver to operate in response to
instructions transmitted from outside the release assembly (e.g.,
via reception of signals transmitted from outside the patient's
body). The release unit 30 may also, in some embodiments, respond
to an input from a biosensor implanted within the patient's body to
influence control over the drug release regimen.
[0027] As shown, one drug release unit 30 of the present invention
has an inlet 30a that receives fluid from the pump, and an outlet
30b leading to the distal catheter. These adapt the controlled
release unit so that when it releases its drugs, these enter the
fluid pathway.
[0028] One suitable arrangement to adapt a microchip drug delivery
device for such operation is to add a cover plate (not shown) over
the unit 30, forming a flow manifold that channels fluid from the
inlet 30a so that it passes over all or appropriate ones of the
release sites 31, 33, 35, and to the outlet 30b. The manifold may
be an active manifold, with different flow channels actively
switched open or closed (for example, by micromechanical valve,
electric field control or other means) to effectively channel fluid
only over the desired release sites (when a passive release
mechanism is used), or only over the device's current active
release site(s) (when an electrically-actuated release structure is
used). Alternatively, the manifold may be a passive assembly of
sufficiently small volume and open shape that the carrier fluid
provided at the inlet effectively washes over all reservoirs at
once, receiving drugs from the activated release sites before
passing to the outlet. In accordance with one aspect of the present
invention, the pump assembly provides a flow of carrier fluid
through the release device that is effective to increase the
pressure locally at the region of the catheter distal outlet ports,
where the catheter is implanted in tissue, creating a pressure
gradient that drives bulk transport of the drug into the target
tissue site. The carrier fluid thus serves as a quantifiable bulk
medium for pressure delivery to move the small quantity of released
drug to the tissue site and to establish a pressure gradient to
enhance delivery at the tissue site. As such, the drug is delivered
as a convection-enhanced, or pressure gradient-driven permeation of
the target tissue, as described, for example, in U.S. Pat. No.
5,720,720. For a typical implanted brain catheter delivery route,
such pressure gradient transport may be achieved with a flow rate
of about one-half (0.5) to about twenty (20.0) microliters per
minute, preferably about 2.0 to 15.0 microliters/minute, and most
preferably about ten microliters/minute (per implanted delivery
tube). When the target site is another type of tissue, such as
pancreatic tissue, the density and other features of the tissue
will determine suitable delivery rates. These may, for example,
vary when the target tissue is tumorous, in dependence upon the
tumor tissue characteristics. It is expected that after suitable
observations, the relevant properties may be correlated with or
characterized by known data, such as the tumor type or stage.
[0029] Delivery of the drug or bioactive material may be sustained
in cycles of several minutes, or may in some instances be
continuous, or may be triggered for relatively short periods in
response to detection of a condition. It will be understood that
the precise rates and durations may depend upon a variety of
factors, including the identity and concentration of the drug or
bioactive material and carrier, the size and tissue properties of
the target site, and the size of the delivery catheter and its
ports, and the number of delivery catheters. Thus, flow rates above
and below the indicated range may also be effective.
[0030] The pump flow may be set and the pump assembly actuated
based upon modeled properties such as histological tissue traits,
drug and fluid viscosity, catheter and port dimensions and the
like, or the pump flow may be governed by one or more extrinsic
inputs, e.g., by a controller operative on input signals from
sensors that detect pressure or flow at relevant locations, or
biosensors that provide other indicia relevant to selecting the
rate for achieving and maintaining the desired drug delivery
conditions.
[0031] An embodiment of the system may be formed using a
conventional infusion pump for the pump assembly 20 as shown in
FIG. 1, and a controlled release drug delivery chip 32, with
suitable flow segments for interconnecting the two units and for
delivering the flow to the target tissue site. There may be more
than one delivery catheter, and these may be connected to different
target tissue sites T1, T2, T3 as shown in FIG. 1A. The sites T1,
T2, T3 may be selected on different sides (e.g., distributed around
the perimeter) of a single targeted tissue site (e.g., a tumor,
gland or organ) so as to maximize the effective treatment volume.
Alternatively, the sites may be distinct, independently targeted
sites, for example, to treat plural distinct lesions, tumors or
disease sites in the brain. Systems of the invention may employ one
or more sensors that provide output signals upon which the
controller operates to determine a pumping or drug release regimen.
The sensors may sense fluid pressure, detect the level or presence
of a substance, a drug or a metabolite, or detect a physiologic
condition to which the treatment is applied. Advantageously, an
array of sensors may themselves be implanted at positions to
determine the spatial distribution in the target tissue of the drug
delivered by the delivery system, and a processor or controller may
operate accordingly to achieve the deliver the desired dose or
concentration distribution, or to achieve the desired control of
sensed conditions during changing metabolic and tissue states. One
such array of sensors is schematically shown in FIG. 1A, and these
may connect to the pump controller (if one is provided) and/or the
controller of the release device (if present). Depending on the
overall system configuration and the type of sensing elements, the
sensor outputs may be subjected to various processing or simple
thresholding operations, for detection of response conditions to
which the system control is directed.
[0032] Advantageously, the invention may also be practiced with a
system 100 as shown in FIG. 2. In this system, a infusion pump 120
connects to a delivery catheter 140 that forms a flow path
extending to and implanted in parenchymal tissue. A plurality of
controlled release drug reservoirs 130a, 130b are formed directly
in the wall of the catheter. The reservoirs may be actuated by
control electrodes connected with control signal leads (not shown)
embedded in the catheter wall. This construction has the advantage
that dead space and lag time are minimized, and the flow path may
have a short length. Thus, the flow conditions are well suited to
assure that the released drugs are reliably entrained in the pumped
flow of carrier fluid without the need for a specially-designed
manifold to interface the flow with the geometry of the drug
release unit, and without requiring a special chip geometry to
enhance mixing. Drug release may be initiated out of phase with
pumping, to assure that the drug is released into the fluid
residing in the catheter before the flow is initiated, so that a
higher concentration is achieved in the carrier fluid, and all drug
is flushed by the flow to provide complete drug delivery.
[0033] The drug release or microchip release unit, whether
configured in a static release configuration or a powered unit
subject to active control by a microcontroller or other circuit,
may be readily configured to administer multiple drugs in a drug
cocktail, with the times and concentrations of each element
accurately controlled. The delivery at higher than normal pressure
at the distal catheter assures an increased rate of drug
penetration of the target site, for example, within the parenchyma
of the brain, while the use of a physiologically inert carrier as
the pump refill enhances overall safety. By configuring the drug
reservoirs in the wall of the catheter (or further by providing the
reservoir portion as a separate short replaceable length or segment
of the catheter) a defined drug cocktail may be provided with the
time and durations of administration of its components accurately
fixed, and their delivery to the exact target site assured.
Advantageously, extended treatment regimens may thus be
implemented, requiring a return office visit only to replenish the
pump's carrier fluid reservoir (for example, when using a
transdermally-refilled bellows-type infusion pump embodiment).
[0034] FIG. 2A illustrates another construction similar to that of
FIG. 2. In this embodiment, a carrier pump 120' connects to a
delivery catheter 140', and a release cartridge 130' fits within
the catheter to provide a controlled release of one or more drugs
or bioactive materials into the pumped carrier fluid. The release
cartridge 130' may be solid body made of a drug with a solid binder
that releases the drug at a defined rate, or may be a construct
such as a permeable-walled cylinder that is loaded with liquid or
solid treatment material and controls release of the material via
the permeability of its walls. The replaceable release cartridge
may have a single active agent or may contain a "cocktail" of
agents, and may be compounded with different binders, particle
coatings and the like to regulate the release of different agents
at different concentrations, rates and/or times. In this regard,
the cartridge 130' may be situated within a portion of the catheter
body catheter 140' having a defined dimension and fluid capacity,
and the cartridge may be formulated such that it quickly reaches
equilibrium salvation, or otherwise attains a defined endpoint or
concentration in the surrounding (known) volume of carrier fluid.
This allows the drug doses to be well controlled, and permits the
remaining cartridge capacity to be reliably calculated as a simple
function of pumping cycles, enhancing the precision of long-term
drug administration and treatment. In particular, such precise
control of the cartridge lifetime assures that the cartridge will
not be unnecessarily replaced before it is exhausted (which would
result in excessive minor surgeries) nor will it remain implanted
after being prematurely exhausted (which would result in a period
of lack of treatment drug).
[0035] It is not necessary that the controlled release drug unit be
situated directly in the delivery line as shown in the foregoing
Figures; rather, it may communicate with the delivery line. FIG. 1B
illustrates an system 10' wherein the release unit 30' is in fluid
communication with the delivery line 40' from the infusion pump 20
at a line junction 41. In this embodiment, the release unit may be
fabricated with a source or mechanism for providing a small but
sufficient flow of fluid to move the released drug along a junction
line 42 into the delivery tube 40'. For example, it may have a
permeable membrane on a side away from the junction line 42 to
provide osmotic ingress of fluid, or other suitable means for
moving it's released drug along the junction line 42.
[0036] In accordance with another aspect of the invention, systems
may be configured to utilize a native bodily fluid as the pump's
carrier fluid. The native bodily fluid may, for example, be the
body's cerebrospinal fluid (CSF) when the targeted tissue is in the
central nervous system. In this embodiment, the infusion pump need
not necessarily possess a reservoir. FIG. 3 schematically
illustrates such a system 200.
[0037] As shown in FIG. 3, a system 200 in accordance with this
aspect of the invention includes a pump 220 that has an inlet port
connected to an inlet catheter uptake assembly 215 that resides in
the patient's cerebrospinal fluid. The inlet catheter may, for
example, be positioned near the base of the skull in the occipital
region, and may have a suitable sump or head structure into which
the CSF infiltrates. The CSF passes along the inlet catheter into
the pump, and is actively pumped at the selected rate and times to
the drug release unit 230 and along the delivery catheter 240 to
the target tissue site. The release unit and delivery catheter may
be separate, or the release unit may be integrated in the catheter
or into the catheter wall as described above in regard to FIGS. 2
and 2A. The inlet catheter may be positioned in the sub-arachnoid
space of the brain or spine, or other suitable position in the CNS.
Preferably the inlet catheter assembly 215 draws fluid from a
region sufficiently remote from the target tissue site, and at a
rate such that the withdrawal of CSF does not create a negative or
counter-acting pressure gradient that would alter or have any
adverse effect on the convective drug delivery to the target tissue
site at the outlet of the delivery catheter 240. That is, the inlet
is positioned so that it does not counteract the positive gradient
produced by the outlet(s) of the delivery catheter(s), or steal
drug from the convectively-enhanced transport into parenchymal or
other CNS tissue that occurs at the target site.
[0038] Systems of the invention may also be implemented to use
other endogenous fluids as the carrier, such as blood, blood serum
or lymphatic fluids, in which case the inlet catheter is positioned
accordingly to collect such other fluid.
[0039] FIG. 3A schematically illustrates other features of a
further system 300 of the present invention. As shown, system 300
has a pump assembly 320 that pumps fluid (either from an inlet as
described above or from a reservoir) into a delivery catheter 340.
The pump assembly includes or communicates with a chamber 302 that
contains a concentrated delivery agent. Chamber 302 supplies the
agent at an appropriate dilution in the carrier fluid. The delivery
agent may, for example, be a morphine, and the pump may deliver its
output to the intrathecal space for pain management. Alternatively,
the delivery agent may be another drug, adjuvant or the like.
[0040] System 300 also has a mixing chamber 304 in line with the
fluid pumping path. Fluid carrying drug released by the chamber 302
and/or released by the controlled release device 330 mixes in the
chamber 304 before entering the delivery catheter 340. This is a
particularly advantageous construction for delivering a drug that
must have a defined concentration, or for delivering pairs of drugs
that must be combined shortly before delivery. The mixing chamber
may be connected to receive material directly from the sources 302,
330, or it may be shaped and dimensioned to passively mix (e.g., by
turbulence, or by solution) the fluid in the fluid path. In some
embodiments, the mixing chamber may be provided with one or more
additional openings and interconnections between ports, and these
are coordinated with the pump or the flow in the delivery line to
recirculate fluid through the chamber and enhance active
mixing.
[0041] Thus, systems of the invention advantageously provide a drug
or multi-drug infusion system that achieves enhanced delivery while
employing a simple pump that advantageously uses a single, inert
carrier fluid, and coordinates or couples its delivery with a
controlled release drug device. By separating the physical delivery
parameters via a pump mechanism from the substance/dose aspects of
medication via the controlled release unit, the system provides a
robust system that achieves enhanced drug distribution in the
target tissue. It also permits various modular forms that result in
more accurate implementation of multi-drug and/or multi-rate
treatment regimens, as well as regimens having a varying range or
schedule responsive to sensor measurements. It also provides a
system architecture in which upstream bulk flow components may be
more accessible and reduce the potential for indwelling incidents
of sepsis or adverse physiological reaction. Moreover, while some
drugs may suitably be compounded in the carrier fluid itself, the
controlled drug release device enables the use of a wide range of
other drugs which, by way of example, may be too unstable for long
term storage in solution. Thus, the architectures of the present
invention in those cases effectively compound the drug for delivery
at the time of release, potentially augmenting the pharmacopoeia
available for implanted delivery systems.
[0042] When the controlled released unit is a powered unit that
relies on applying electrical signals to initiate release from each
reservoir at appropriate times, these release signals may be
coordinated with the pumping intervals to maximize the drug
concentration in pumped fluid for the selected volume and rate of
convective delivery. In particular, by initiating drug release into
the restricted space of the flow path before starting pumping of
the carrier, a highly concentrated fluid is delivered at a precise
time and at an overpressure condition at the catheter outlet,
without slow ramping-up of the release characteristics, and without
allowing diminution by the body's initial clearance or breakdown
mechanisms such as occurs in the prior art release devices. Thus,
coordinating the release and the pumping cycles may maximize the
initial concentration as well as the rate of transport into the
target tissue site. Moreover, when utilizing an electrically
controlled infusion pump, the timing and control signals for the
release unit may be provided from the pump controller, allowing a
range of modular constructions wherein a release unit having
particular drugs or treatment materials "plugs in" to a pump unit
having the desired delivery characteristics, and also having
suitable control cycles programmed therein.
[0043] It will be understood that the term "drug" as used herein
and in the attached claims refers not simply to complex organic
chemicals, but is intended to mean any biologically relevant
material that is to be delivered to a target tissue site. As such,
it may include pharmaceutical compounds; treatment organisms;
treatment fluids; cellular products, components or materials; label
or probe material; and genetic sequence material among others.
Furthermore, the term "carrier fluid" may be any compatible fluid
that may be pumped at a rate effective to provide convective
delivery of the drug into tissue. As such, it may be a fluid such
as a physiological buffer or saline solution, an endogenous fluid
or component thereof, such as blood plasma or cerebrospinal fluid.
It may also involve various pharmaceutical preparations, such as
excipients and adjuvants, or a combination of different ones of the
foregoing fluids.
[0044] The invention being thus disclosed and several illustrative
embodiments described, modifications, variations and adaptations
thereof will occur to those skilled in the art, and all such
variations, modifications and adaptations are considered to be
within the scope of the invention as defined herein and in the
appended claims and equivalents thereof. All patents and references
disclosed above are expressly incorporated herein by reference in
their entirety.
* * * * *